Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial

G207 is a conditionally replicating derivative of herpes simplex virus (HSV) type-1 strain F engineered with deletions of both gamma(1)34.5 loci and a lacZ insertion disabling the UL39 gene. We have demonstrated the efficacy of G207 in treating malignant glial tumors in athymic mice, as well as the safety of intracerebral G207 inoculation in mice and in Aotus nancymai. We sought to determine the safety of G207 inoculation into cerebral malignant glial tumors in humans. Criteria for inclusion into this dose-escalation study were the diagnosis of histologically proven malignant glioma, Karnofsky score > or = 70, recurrence despite surgery and radiation therapy, and an enhancing lesion greater than 1 cm in diameter. Serial magnetic resonance images were obtained for volumetric analysis. The trial commenced at a dose of 10(6) plaque forming units (p.f.u.) inoculated at a single enhancing site and was completed when the 21st patient was inoculated with 3x10(9) p.f.u. at five sites. While adverse events were noted in some patients, no toxicity or serious adverse events could unequivocally be ascribed to G207. No patient developed HSV encephalitis. We found radiographic and neuropathologic evidence suggestive of anti-tumor activity and long-term presence of viral DNA in some cases.     

Combination suicide/cytokine gene therapy as adjuvants to a defective herpes simplex virus-based cancer vaccine

We have used syngeneic, established bilateral subcutaneous tumor models to examine the antitumor activity of herpes simplex virus (HSV) vectors, including the induction of an immune response against non-inoculated distant tumors. In such a model with CT26 murine colon adenocarcinoma, unilateral intratumoral inoculation of replication-deficient HSV-1 tsK inhibited the growth of both the inoculated and noninoculated established tumors. To enhance this limited antitumor immune response, we generated a defective HSV vector, dvIL12-tk encoding both interleukin-12 (IL-12) and HSV thymidine kinase (TK), with tsK as the helper virus. In a 'suicide gene' strategy, ganciclovir (GCV) treatment after intratumoral inoculation of dvlacZ-tk/tsK, encoding E. coli lacZ instead of IL-12, resulted in enhanced antitumor activity. Antitumor activity was also enhanced by local expression of IL-12 from dvIL12-tk/tsK. The combination of IL-12 cytokine therapy with GCV treatment was the most efficacious approach, with significantly greater inhibition of tumor growth than IL-12 or TK + GCV alone. These results illustrate the power of combining different cancer therapy approaches; 'suicide gene' therapy, cytokine therapy, and HSV vector infection. HSV vectors are particularly well suited to this because they can accommodate the insertion of large and multiple gene sequences.     

骨纤维结构不良的诊断和治疗进展

目的:对长期以来关于骨纤维结构不良大量相关研究及文献进行回顾,综述骨纤维结构不良的诊断和治疗的最新进展。资料来源:通过计算机互联网检索OVID数据库1966-01/2006-10关于骨纤维结构不良的文献,检索词:Osteofibrous dysplasia,限定语言种类为English。同时检索1994-01/2006-10中国全文期刊数据库有关骨纤维结构不良的文献,检索词为:骨纤维结构不良,限定语言种类为中文。资料选择:选择与骨纤维结构不良相关的观察对比研究、经验总结、个案报道、最新研究进展等文献,力求资料全面,排除重复研究。资料提炼:共收集相关国内外文献41篇,排除重复性研究11篇,采用30篇,包括关于骨纤维结构不良定义、发病机制、病理、诊断及治疗等。资料综合:①骨纤维结构不良是一种起源于纤维组织的良性骨肿瘤。发病率低、误诊率高。目前具体发病机制不明,现认为与常染色体显性遗传有关。②骨纤维结构不良好发于胫骨,症状为局部肿块。特征性影像学表现为胫骨中段前侧皮质膨胀性密度减低。确诊方法为病理检查。重点与骨纤维异常增殖症、造釉细胞瘤相鉴别,现有大量研究证明该病与造釉细胞瘤有联系。③治疗上过去认为10岁以前应保守治疗,10岁后选择手术治疗,目前倾向于早期骨膜外切除手术治疗。结论:骨纤维结构不良发病率低,对该病认识较少,误诊率较高,重点需与骨纤维异常增殖症、造釉细胞瘤相鉴别,应提高对该病的认识与重视程度,对可疑者行病理检查,确诊者行骨膜外切除,切除范围较大的病例行重建手术。     

A randomized clinical trial comparing behavior modification and individual counseling in the nutritional therapy of non-insulin-dependent diabetes mellitus: comparison of the effect on blood sugar, body weight, and serum lipids

To determine whether a group behavior modification approach might be preferable to individual counseling in the nutritional therapy of non-insulin-dependent diabetes mellitus, 40 adults younger than 65 yr of age with diabetes mellitus who were not receiving insulin were randomized to either a program of individualized dietary review and recommendations or a program of group meetings aimed at controlling the signals leading to overeating and noncompliance with a diabetic dietary regimen. Statistically significant (P less than 0.05) decreases in body weight, sum skin-fold thickness, fasting serum glucose, and serum triglycerides but not LDL-C or HDL-C were observed. The individual counseling group had a greater amount of weight loss than the behavior modification group. There were no significant (P greater than 0.05) differences between the two groups with respect to the biochemical outcome variables. Patient characteristics assessed at entry--namely anxiety, internal versus external locus of control and perceived disease severity, and compliance with advice--were significantly associated with weight loss in the behavior modification group while only the latter index was of value in the individual counseling group. Thus, our use of these programs does not identify a clear advantage of either approach in the nutritional therapy of non-insulin-dependent diabetic patients.     

Hepatic and cardiac iron overload among patients with end‐stage liver disease referred for liver transplantation

O’Glasser AY, Scott DL, Corless CL, Zaman A, Sasaki A, Gopal DV, Rayhill SC, Orloff SL, Ham JM, Rabkin JM, Flora K, Davies CH, Broberg CS, Schwartz JM. Hepatic and cardiac iron overload among patients with end‐stage liver disease referred for liver transplantation.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01136.x.
© 2009 John Wiley & Sons A/S. Abstract: Background: Iron overload is associated with fatal cardiovascular events following liver transplantation. Myocardial iron deposits were observed post‐mortem in patients who died of cardiac events after transplantation at our institution. This observation prompted testing to exclude cardiac iron in subsequent transplant candidates. Aims: To assess the results of testing for iron overload in liver transplant candidates at our institution. Methods: Ferritin, TIBC, and serum iron were measured in cirrhotics referred for transplantation. Patients with transferrin saturation ≥50% and ferritin ≥250 ng/mL underwent liver biopsy graded for iron. Patients with 3–4+ hepatic iron deposits underwent HFE mutation analysis and endomyocardial biopsy with iron staining. Results: Eight hundred and fifty‐six patients were evaluated for liver transplantation between January 1997 and March 2005. Two hundred and eighty‐seven patients (34%) had transferrin saturation ≥50% and ferritin ≥250 ng/mL. Patients with markers of iron overload had more advanced liver disease than those with normal iron indices. One hundred and fifty‐three patients underwent liver biopsy. Twenty‐six patients (17%) had 3–4+ hepatic iron staining. One patient was a C282Y heterozygote. Endomyocardial biopsy was performed in 14 patients of whom nine had cardiac iron deposition. Conclusions: Non‐HFE‐related cardiac iron overload can occur in advanced liver disease We therefore recommend screening for cardiac iron prior to liver transplantation.